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image of Interferon Causes Endothelial Injury in Humans

Abstract

Therapy with exogenous interferon and human conditions that feature endogenous interferon upregulation may be associated with endothelial damage that primarily involves small blood vessels. Endothelial injury associated with interferon may display different clinical expression, including thrombotic microangiopathy, Raynaud’s phenomenon, vasculopathy of dermatomyositis and atrophic papulosis, interferon-associated skin angiopathy, systemic capillary leak syndrome, collapsing glomerulopathy, interstitial lung disease, pulmonary hypertension, and retinopathy. Interferon-induced endothelial damage involves complement-mediated injury, although pathogenic mechanisms by which interferon promote abnormal complement activation on endothelial cells are not fully understood. Human interferon-γ (type II interferon) binds to heparan sulfate on the endothelial surface, suggesting that overproduction of interferon-γ may hinder factor H attachment to the same location. Absence of factor H on self surfaces promotes activation of the alternative pathway of complement and complement-mediated endothelial damage. Type I interferon typically induces the generation of antibodies. Type I interferon upregulation may elicit the formation of autoantibodies against factor H. These autoantibodies block factor H binding to endothelial surfaces, abolishing the protective effect of factor H on complement-mediated damage. In addition, interferon induces insulin resistance which is associated with reduced heparan sulfate in the extracellular matrix, including the endothelial surface. Decreased amount of heparan sulfate suppresses factor H attachment, promoting activation of the alternative pathway of complement. Complement blockade with eculizumab (a monoclonal antibody against C5) improves endothelial damage in patients with thrombotic microangiopathy and other situations associated with interferon upregulation and interferon-induced endothelial injury, suggesting that complement-mediated injury is clinically relevant under conditions that feature interferon overproduction.

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2024-10-07
2024-11-26
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